Characterization of heart failure in aged LPA1/2 double knock out mice

Lysophosphatidic acid (LPA) is a bioactive lipid molecule in serum that acts, at least in part, by binding to four G‐protein coupled receptors, termed LPA 1 – 4. Relatively little is known about how LPA effects on the heart. We observed high levels of LPA 1 and 2 mRNAs in mouse heart, and therefore, investigated LPA’s physiological effect on the heart by use of LPA1/2 double knock out (DKO) mice. By echocardiography, systolic left ventricular function in the LPA1/2 DKO mice declined with age [7% ± 0.7 fractional shortening (FS) at age 13–14 mo], but not in either LPA1 (29% FS ±0.2 at 14–17 mo) or LPA2 (30% FS at 15 mo) single knock out mice. The first manifestation of heart failure appeared to be enlargement of the right ventricle in the LPA1/2 DKO. Direct pressure measurements indicated higher systolic right ventricular pressures in LPA1/2 DKO mice (57 vs. 25 ± 5 mmHg in wild‐type), while the systemic blood pressure (130 ± 23 mmHg) and heart rate (627 ± 51 bpm) in the DKO mice were not different from wild‐type (130 ± 20 mmHg and 612 ± 37 bpm). Examination of the lung failed to reveal extensive pulmonary vascular remodeling, although calcification and airway hemorrhage were observed. Thus, deficiency of LPA receptors 1 and 2 results in right ventricular hypertrophy and age‐dependent left ventricular failure, suggesting a role for these receptors in normal heart physiology. Source of support: NIH R01 HL078663